Antibacterial and Cytotoxic Actinomycins Y6-Y9 and Zp from Streptomyces sp. Strain Gö-GS12

Wenlong Cai; Xiachang Wang; Sherif I. Elshahawi; Larissa V. Ponomareva; Xiaodong Liu; Matthew R. McErlean; Zheng Cui; Ashley L. Arlinghaus; Jon S. Thorson; Steven G. Van Lanen

doi:10.1021/acs.jnatprod.6b00742

Antibacterial and Cytotoxic Actinomycins Y₆-Y₉ and Zp from Streptomyces sp. Strain Gö-GS12

Wenlong Cai, Xiachang Wang, Sherif I. Elshahawi, Larissa V. Ponomareva, Xiaodong Liu, Matthew R. McErlean, Zheng Cui, Ashley L. Arlinghaus, Jon S. Thorson, Steven G. Van Lanen

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Four new Y-type actinomycin analogues named Y₆-Y₉ (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain Gö-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y₅ and other actinomycins.

Original language	English
Pages (from-to)	2731-2739
Number of pages	9
Journal	Journal of Natural Products
Volume	79
Issue number	10
DOIs	https://doi.org/10.1021/acs.jnatprod.6b00742
State	Published - Oct 28 2016

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health Grants AI087849 (S.V.L.), AI52188 (J.S.T.), and OD21479 (J.S.T.); the National Center for Advancing Translational Sciences Grant UL1TR000117 (S.V.L. and J.S.T.); the University of Kentucky College of Pharmacy (S.V.L. and J.S.T.); and the University of Kentucky Markey Cancer Center (J.S.T.)

Publisher Copyright:
© 2016 The American Chemical Society and American Society of Pharmacognosy.

ASJC Scopus subject areas

Analytical Chemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Complementary and alternative medicine
Organic Chemistry

Access to Document

10.1021/acs.jnatprod.6b00742

Cite this

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title = "Antibacterial and Cytotoxic Actinomycins Y6-Y9 and Zp from Streptomyces sp. Strain G{\"o}-GS12",

abstract = "Four new Y-type actinomycin analogues named Y6-Y9 (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain G{\"o}-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y5 and other actinomycins.",

author = "Wenlong Cai and Xiachang Wang and Elshahawi, {Sherif I.} and Ponomareva, {Larissa V.} and Xiaodong Liu and McErlean, {Matthew R.} and Zheng Cui and Arlinghaus, {Ashley L.} and Thorson, {Jon S.} and {Van Lanen}, {Steven G.}",

note = "Funding Information: This work was supported in part by the National Institutes of Health Grants AI087849 (S.V.L.), AI52188 (J.S.T.), and OD21479 (J.S.T.); the National Center for Advancing Translational Sciences Grant UL1TR000117 (S.V.L. and J.S.T.); the University of Kentucky College of Pharmacy (S.V.L. and J.S.T.); and the University of Kentucky Markey Cancer Center (J.S.T.) Publisher Copyright: {\textcopyright} 2016 The American Chemical Society and American Society of Pharmacognosy.",

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AU - Cai, Wenlong

AU - Wang, Xiachang

AU - Elshahawi, Sherif I.

AU - Ponomareva, Larissa V.

AU - Liu, Xiaodong

AU - McErlean, Matthew R.

AU - Cui, Zheng

AU - Arlinghaus, Ashley L.

AU - Thorson, Jon S.

AU - Van Lanen, Steven G.

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PY - 2016/10/28

Y1 - 2016/10/28

N2 - Four new Y-type actinomycin analogues named Y6-Y9 (1-4) were isolated and characterized from the scale-up fermentation of the Streptomyces sp. strain Gö-GS12, as well as actinomycin Zp (5), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of 1 uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of 4 and 5 contain a rare 5-methyl proline. Compounds 2-5 showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in 1 rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y5 and other actinomycins.

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